Genomic landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the CALGB 10603/RATIFY trial Journal Article


Authors: Jahn, N.; Jahn, E.; Saadati, M.; Bullinger, L.; Larson, R. A.; Ottone, T.; Amadori, S.; Prior, T. W.; Brandwein, J. M.; Appelbaum, F. R.; Medeiros, B. C.; Tallman, M. S.; Ehninger, G.; Heuser, M.; Ganser, A.; Pallaud, C.; Gathmann, I.; Krzykalla, J.; Benner, A.; Bloomfield, C. D.; Thiede, C.; Stone, R. M.; Döhner, H.; Döhner, K.
Article Title: Genomic landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the CALGB 10603/RATIFY trial
Abstract: The aim of this study was to characterize the mutational landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the randomized CALGB 10603/RATIFY trial evaluating intensive chemotherapy plus the multi-kinase inhibitor midostaurin versus placebo. We performed sequencing of 262 genes in 475 patients: mutations occurring concurrently with the FLT3-mutation were most frequent in NPM1 (61%), DNMT3A (39%), WT1 (21%), TET2 (12%), NRAS (11%), RUNX1 (11%), PTPN11 (10%), and ASXL1 (8%) genes. To assess effects of clinical and genetic features and their possible interactions, we fitted random survival forests and interpreted the resulting variable importance. Highest prognostic impact was found for WT1 and NPM1 mutations, followed by white blood cell count, FLT3 mutation type (internal tandem duplications vs. tyrosine kinase domain mutations), treatment (midostaurin vs. placebo), ASXL1 mutation, and ECOG performance status. When evaluating two-fold variable combinations the most striking effects were found for WT1:NPM1 (with NPM1 mutation abrogating the negative effect of WT1 mutation), and for WT1:treatment (with midostaurin exerting a beneficial effect in WT1-mutated AML). This targeted gene sequencing study provides important, novel insights into the genomic background of FLT3-mutated AML including the prognostic impact of co-mutations, specific gene–gene interactions, and possible treatment effects of midostaurin. © 2022, The Author(s).
Keywords: adult; cancer survival; controlled study; unclassified drug; gene mutation; gene sequence; major clinical study; mutation; leukemia, myeloid, acute; placebo; cancer combination chemotherapy; cancer patient; genetic analysis; protein function; gene; gene targeting; randomized controlled trial; genetic association; gene frequency; cytogenetics; protein tyrosine kinase; mutational analysis; information processing; protein tyrosine kinase inhibitor; gene interaction; genomics; allogeneic hematopoietic stem cell transplantation; leukocyte count; wt1 protein; informed consent; loss of function mutation; dna determination; protein tyrosine phosphatase shp 2; tet2 gene; transcription factor runx1; dna methyltransferase 3a; clinical trial (topic); asxl1 gene; oncogene n ras; cd135 antigen; nucleophosmin; clinical outcome; midostaurin; acute myeloid leukemia; fms-like tyrosine kinase 3; cancer prognosis; high throughput sequencing; dnmt3a gene; wt1 gene; humans; prognosis; human; male; female; article; runx1 gene; genetic background; flt3 protein, human; ecog performance status; fms-like tyrosine kinase 3 inhibitor; ratify trial
Journal Title: Leukemia
Volume: 36
Issue: 9
ISSN: 0887-6924
Publisher: Nature Publishing Group  
Date Published: 2022-09-01
Start Page: 2218
End Page: 2227
Language: English
DOI: 10.1038/s41375-022-01650-w
PUBMED: 35922444
PROVIDER: scopus
PMCID: PMC9417991
DOI/URL:
Notes: Article -- Export Date: 3 October 2022 -- Source: Scopus
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  1. Martin Stuart Tallman
    640 Tallman